Description

Febrile seizures (FS) occur in children aged 6 months to 5 years with fever ≥100.4°F (38°C) in the absence of an underlying neurologic abnormality, metabolic condition, or intracranial infection. There are three distinct categories (1),(2):

• Simple febrile seizure (SFS) (70–75%; must meet all criteria)
  • Generalized clonic or tonic–clonic seizure activity without focal features
  • Duration <15 minutes
  • Does not recur within 24 hours
  • Resolves spontaneously
  • No history of previous afebrile seizure, seizure disorder, or other neurologic problem
• Complex febrile seizure (CFS) (20–25%; only one criterion must be met)
  • Partial seizure, focal activity
  • Duration >15 minutes but <30 minutes
  • Recurrence within 24 hours
  • Postictal focal neurologic abnormalities (e.g., Todd paralysis)
• Febrile status epilepticus (FSE) (5%)
  • Lasts >30 minutes

Epidemiology

Incidence

• About 500,000 FS in the United States annually.
• Occurs in 2–4% of children 6 months to 5 years of age. Peak incidence is 18 months of age with 90% of children having their first FS before age 3. Only 6% of FS occur before age 6 months (3).
• Bimodal seasonal pattern that mirrors peaks of febrile respiratory (November to January) and gastrointestinal infections (June to August) (4)

Prevalence
Children of any ethnic group can develop FS, but there is higher prevalence in Asian population, specifically the Japanese (3.4–9.3%), Indians (5–10%), and Guamanians (14%). Children in United States and Western Europe have a prevalence of 2–5%.

Etiology and Pathophysiology

The pathophysiology of FS remains unclear but current research suggests the following mechanisms that lower seizure threshold:

• Age-dependent vulnerability of developing nervous system (2)
• Increased neuronal activity (i.e., seizures) secondary to temperature-sensitive ion channels and secretion of cytokines from inflammatory processes such as fever-promoting pyrogen interleukin-1β
  • Interleukin-1β can increase neuronal activity by modulating glutamate and GABA.
• Hyperthermia-induced hyperventilation and alkalosis, which provokes neuronal excitability

Genetics

• FEB1 and FEB2 are known to increase susceptibility to FS.
  • Sodium channel 1alpha (SCN1A) mutation is also known to increase susceptibility to FS; however, epileptic syndromes can also carry the same mutation:
    • Dravet syndrome: most severe form of epileptic encelphalopathy that presents with FS and is commonly caused by a de novo mutation of SCN1A
• Mode of inheritance thought to be through polygenic multifactorial transmission (several different pairs of genes that are contributory and additive to the phenotype) or autosomal dominant pattern with reduced penetrance

Risk Factors

• Most common risk factors for developing first FS (1),(5):
  • Height of fever, more so than rate of rise
  • Viral infection (80% of FS caused by virus)—HHV6, influenza A, adenovirus, and parainfluenza are commonly associated viruses
  • Recently immunized, particularly with MMR and DTwP
  • Family history of FS
    • As many as 25–40% of cases have a positive family history of FS. Risk increases with number of affected first-degree (OR = 4.5%) and second-degree relatives (OR = 3.6%); greater concordance rate in monozygotic than dizygotic twins (1)
• Other general risk factors for FS: nicotine exposure in utero, NICU stay >28 days, developmental delay or day care attendance
• Risk is slightly increased for males (2).
• Recent vaccination (6)
  • Certain vaccines (e.g., MMR, DTP, PCV13), method of preparation, vaccine coadministration, and associated age of administration have shown to increase risk of FS.
  • No evidence of increased risk with isolated influenza vaccination
• Perhaps increased risk with iron deficiency anemia and low zinc levels (1),(4)

General Prevention

Choose vaccines with lower risk of developing FS and ask if the child has ever had a history of FS after vaccine administration (5).

• Increased risk of FS if vaccine administrations are delayed
• Separate MMR and varicella vaccine and administer between 12 and 15 months of age.
• Administer DTaP (acellular) rather than DTwP (whole cell) vaccine.

Commonly Associated Conditions

• Viral infections are the cause of fever in nearly 80% of FS cases, particularly human herpesvirus 6 (HHV-6), influenza, parainfluenza, adenovirus, and respiratory syncytial virus (RSV) (4).
• Bacterial infections: otitis media, pharyngitis, urinary tract infection (UTI), pneumonia, and gastroenteritis (specifically with Shigella)
• Vaccinations (6):
  • MMRV vaccination had 2-fold increase in risk of FS compared to separation of MMR and varicella vaccine.
  • DTwP vaccine had roughly 15% greater chance of causing FS compared to DTaP (1 per 2,835 vaccines and 1 per 19,496 vaccines, respectively).
  • There is a small increased risk for FS when activated influenza vaccine (flu shot) is given at the same time as either the PCV13 (pneumococcal) vaccine or the DTaP vaccine (7).
    • Also small increased risk with PCV13 given alone (7)
    • No increased risk if influenza or DTaP given alone (7)